Complexity of receptor tyrosine kinase signal processing

Abstract

Our knowledge of molecular mechanisms of receptor tyrosine kinase (RTK) signaling advances with ever-increasing pace. Yet our understanding of how the spatiotemporal dynamics of RTK signaling control specific cellular outcomes has lagged behind. Systems-centered experimental and computational approaches can help reveal how overlapping networks of signal transducers downstream of RTKs orchestrate specific cell-fate decisions. We discuss how RTK network regulatory structures, which involve the immediate posttranslational and delayed transcriptional controls by multiple feed forward and feedback loops together with pathway cross talk, adapt cells to the combinatorial variety of external cues and conditions. This intricate network circuitry endows cells with emerging capabilities for RTK signal processing and decoding. We illustrate how mathematical modeling facilitates our understanding of RTK network behaviors by unraveling specific systems properties, including bistability, oscillations, excitable responses, and generation of intricate landscapes of signaling activities.

Figure 1.

Mechanisms of insulin-EGF signal integration. Synergistic ERK activation arises from coincidence detection of insulin and EGF stimuli at the level of GAB1 adaptor protein. GAB1 is massively recruited to the membrane by IR signaling (GAB1→PIP₃-GAB1) and subsequently phosphorylated by EGFR and activated Src (PIP₃-GAB1→PIP₃-pGAB1). (Modified from Borisov et al. 2009; reprinted, with permission, from the authors.)

Figure 2.

Coherent and incoherent feedforward motifs. (A) Basic structure of coherent feed forward loop (coherent FFL [Mangan and Alon 2003]). (B) Schematic representation of ERK-induced c-Fos expression and activation that includes a cascade of coherent FFLs. Active ERK (ppERK) and RSK (pRSK) activate transcription factors required for c-Fos expression and therefore, c-fos mRNA expression. ERK and RSK stabilize and activate the nascent c-Fos protein by phosphorylation making an additional AND gate (based on data from Nakakuki et al. 2010). (C) Basic structure of incoherent feed forward loop of type I (incoherent FFL [Mangan and Alon 2003]). (D) Schematic representation of EGFR regulated c-fos mRNA availability in terms of incoherent FFL. On stimulation, EGFR induces expression of c-fos (B). ZFP36 is also induced by EGFR and mediates c-fos RNA degradation. (Based on data from Avraham and Yarden 2011.)

Figure 3.

Simplified scheme presenting multiple feedback loops in the EGFR pathway. Upon EGFR ligation and activation, protein complexes nucleated by scaffolds are formed at the plasma membrane. Activated Ras induces activation of the Raf-MEK-ERK signaling cascade. Active ERK phosphorylates several upstream signaling regulators, including Raf and SOS, forming negative feedback loops. However, ERK also phosphorylates and inhibits RKIP, which is a negative regulator of Raf, thus creating positive feedback. Active ERK translocates to the nucleus where it phosphorylates several transcription factors, inducing transcription of several IEGs that are negative regulators of EGFR signaling. DUSPs are rapidly induced upon ERK activation, and some DUSPs also require phosphorylation by ERK to become fully active in order to dephosphorylate ERK. Another inducible inhibitor of EGFR, Mig-6, inhibits EGFR by blocking its kinase activity and mediating ubiquitin-independent degradation of EGFR. Several transcription factors induced by EGFR, such as MafF, inhibit transcription of genes that contain SRE in the promoter. Additional mechanism of negative regulation is mediated by ZFP36 that binds to the AU-rich 3′-UTR of mRNA molecules, such as c-fos mRNA and other IEG, targeting them for degradation. Dashed arrows represent indirect or unknown regulation; blue arrows represent mechanisms involving transports between the cytoplasmic and nuclear compartments.